The activation of T lymphocytes (T cells) is tightly regulated by the immune system to ensure rapid responses to pathogens while avoiding reactions against innocuous environmental and self-antigens. One mechanism used to regulate responses of peripheral cells is T cell anergy. Anergy is characterized by defects in T cell proliferation and IL-2 secretion, and results from stimulation in the absence of inflammatory or costimulatory signals. Studies in T cell clones have identified several signaling pathways that are perturbed in anergic cells, and these include Ras/MAPK signaling, calcium flux, Fyn kinase activity, and cAMP signaling. Far less analysis has been done on primary T cells, and there appear to be significant differences between signaling in anergic primary T cells and anergic clones. To further analyze anergy in primary T cells, a mouse model system has been developed, combining the antigen-specificity of TCR transgenics with the anti apoptotic properties of a Bcl-xL transgene. This model is compatible with multiple anergy induction protocols, and overcomes many difficulties associated with biochemical analysis of primary T cells. The goal of this project is to investigate the signaling events involved in regulating anergy in primary T cells. Both in vitro and in vivo models of anergy will be studied. A particular interest will be taken in differences between signaling events in various modes of anergy induction, and in the requirements for maintenance of the non-responsive state. The long-term objective of this research is the application of increased understanding of the processes involved in T cell anergy, along with the ability to manipulate these processes, to novel therapeutic approaches for diseases of aberrant immune function, such as autoimmunity, and the improvement of immune therapy for cancer.